CN108653287B - Application of sinomenine in preventing and treating thoracic aortic dissection/aortic aneurysm - Google Patents
Application of sinomenine in preventing and treating thoracic aortic dissection/aortic aneurysm Download PDFInfo
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Abstract
The invention relates to an application of sinomenine in preparing a medicament for preventing and/or treating thoracic aortic dissection/aortic aneurysm, which comprises the following components in part by weight: drugs administered via the gastrointestinal tract, drugs administered via intravenous injection, drugs administered by subcutaneous embedding administration, preferably drugs administered by subcutaneous embedding administration.
Description
Technical Field
The invention belongs to the field of medical biology, and particularly relates to application of sinomenine in prevention and treatment of thoracic aortic dissection/aortic aneurysm.
Background
Aortic dissection and aortic aneurysm are the most common fatal aortic diseases. The aortic dissection refers to a disease that blood tears the intima of the aortic wall and enters the media to form a false lumen. Aortic aneurysm refers to the expansion and expansion of aorta in a balloon shape with diameter increased by more than 50% due to injury of arterial wall and elasticity reduction caused by inflammation and atherosclerotic plaque. The aortic dissection disease develops quickly, and once the aortic dissection is broken, the death rate is up to 80 percent; the aortic aneurysm is hidden, and most patients have extremely violent disease conditions when clinical symptoms appear. Early prevention and timely treatment is particularly important for aortic dissection and aortic aneurysms.
The traditional treatment method of aortic dissection and aortic aneurysm is a thoracoabdominal open operation, but the operation trauma is large, the perioperative death rate is high (25%), and the postoperative complications are many. In addition to surgical treatment, intraluminal repair (TEVAR) and pharmaceutical intervention are also common modalities for treating aortic aneurysms and aortic dissections. In fact, most low-risk patients can well control the disease condition only by using drug treatment. Therefore, the medical drug therapy can become an independent treatment method, is also the basic treatment of aorta covered stent endoluminal isolation or surgical operation, and is an important treatment means for preventing recurrence for a long time.
The current commonly used drugs for clinically treating aortic aneurysm and aortic dissection include epinephrine β receptor blocker (β receptor blocker), angiotensin II receptor 1 antagonist, angiotensin converting enzyme inhibitor, statins, etc. mainly play roles in controlling blood pressure, reducing heart rate, stabilizing hemodynamics, etc. without prevention and treatment from the pathogenesis of aortic dissection and aortic aneurysm itself, for example, β receptor blocker delays the expansion of thoracic aortic aneurysm, reduces the incidence of vascular rupture and thoracic aortic dissection by reducing blood pressure and myocardial contractility, thereby reducing blood vessel wall tension, angiotensin II receptor 1 antagonist is a commonly used antihypertensive drug that inhibits the binding of angiotensin II and its receptor 1, and there are some adverse reactions and side effects, such as β receptor blocker may cause urinary retention, intestinal paralysis, blurred vision, etc. statins have liver and kidney toxicity, etc.
Aiming at the problem, the inventor of the application screens common traditional Chinese medicine components or compounds of plant sources through an animal model to obtain a new medicine which can be used for treating aortic aneurysm and aortic dissection.
Disclosure of Invention
The invention firstly relates to the therapeutic application of sinomenine to thoracic aortic dissection/thoracic aortic aneurysm, which is to administer sinomenine in a mode of injection administration for clinically confirmed thoracic aortic dissection/thoracic aortic aneurysm patients. Preferably, the sinomenine is sinomenine hydrochloride.
The invention also relates to the application of the sinomenine in preparing a medicament for treating the thoracic aortic dissection/thoracic aortic aneurysm, wherein the medicament comprises but is not limited to a medicament for being administered through a gastrointestinal tract, a medicament for being administered through intravenous injection and a medicament for being administered in a subcutaneous embedding mode. Preferably, the sinomenine is sinomenine hydrochloride.
The invention also relates to the application of the sinomenine in preparing a medicament for preventing thoracic aortic dissection/thoracic aortic aneurysm, wherein the medicament comprises but is not limited to a medicament for being administrated through gastrointestinal digestive tract, a medicament for being administrated through intravenous injection and a medicament for being administrated in a subcutaneous embedding administration mode. Preferably, the sinomenine is sinomenine hydrochloride.
Drawings
Figure 1, effect of sinomenine on prevention of thoracic aortic dissection/aortic aneurysm in mouse model.
FIG. 2 therapeutic Effect of sinomenine on thoracic aortic dissection/aortic aneurysm of mouse model
Detailed Description
Experimental animal, reagent, kit and instrument
Laboratory animal
Thoracic aortic dissection/aortic aneurysm model: the 3 week old male wild type mice (C57BL/6) were purchased from Beijing Huafukang Biotech GmbH. All animals were bred in the SPF-level environmental animal house of the institute of cardiovascular and cerebrovascular diseases, Beijing. The wild mouse is a male mouse which is 3 weeks old and has the weight of about 10 g. All experimental procedures were performed according to the experimental procedures specified in the guidelines for the management and use of laboratory animals, established in NIH and 1996, and the Committee for the management of laboratory animals of the university of capital medicine. All experimental animals were grouped according to a randomized method.
Biochemical reagents and kit names and suppliers are given in Table 1 below
TABLE 1 Biochemical reagent and kit names and suppliers
The names of the laboratory instruments and the suppliers are shown in Table 2 below
TABLE 2 Experimental instruments, Equipment names and suppliers
Example 1 construction of thoracic aortic dissection/aortic aneurysm mouse model (mouse TAD model)
Construction and evaluation of TAD model of BAPN water feeding group mice
A male mouse with 3 weeks old and C57BL/6 background is taken and given a normal diet,
BAPN water feeding group (n ═ 16): BAPN was dissolved in drinking water at a dose of 1 g/kg/day.
On day 14 of BAPN feeding, 5 mice were randomly selected for thoracic aortic ultrasonography to determine whether there had been thoracic aortic broadening/dissection. After repeated experiments, some mice had developed aortic arch thickening and slight dissection at day 14 and began to die in succession. The evaluation scheme of the effect of the model induced dissecting/aneurysm is as follows:
1. the aorta of the dead mouse is dyed by HE or elastic fiber (the specific method is shown in example 2), and whether the diameter of the vessel is thickened or not is measured (interlayer); or observing whether the disorder of the elastic plate or the aneurysm appears;
2. the living mice were subjected to aortic arch ultrasonography, and the diameter was calculated to see whether thickening or dissection occurred.
BAPN water fed group mice were perfused with AII 4 weeks later: subcutaneous infusion was performed at a dose of 1 μ g/kg for 24 hours, as was not killed 24 hours after AII infusion, and sacrificed collectively.
Example 2 preventive Effect of Sinomenine administration on aortic dissection/aortic aneurysm
Sinomenine is ordered from Zhongnong Boxin (Beijing) science and technology Limited, with the product number being BP1314, and the specific name being Sinomenine hydrochloride (Sinomenine hydrochloride)
TAD mouse models were constructed using the BAPN feeding method as described in example 1.
TAD-induced mice were randomly divided into two groups,
one group is a sinomenine experimental group: intraperitoneal injection of sinomenine is carried out once every two days from the first day of BAPN water feeding according to the dose of 150 mg/kg;
the other group was a control group: the same volume of saline was administered by intraperitoneal injection at the same frequency as in the sinomenine-treated group.
Four weeks later, both groups of mice were given angiotensin ii (aii) pump charges for 24 h.
Post-dose observations include:
1. weight: two groups of mice were weighed daily. Observe whether the drug affects body weight versus growth.
BAPN uptake: observing the drinking conditions of the two groups of mice approximately every day, and judging whether the drug affects the weight change of the mice
3. Blood pressure changes: blood pressure measurements were taken every 3 days from the third week to exclude the effects of blood pressure changes on the risk of aneurysm \ dissection rupture and survival of mice
And (4) observing an end point:
1. mice spontaneously died during molding: record the time and cause of death (whether or not death was due to dissection/aneurysm rupture);
2. non-dead mice: performing aortic arch portion ultrasound on the living mouse 24h before pumping, and counting the diameter of a blood vessel; the mice were sacrificed 24h after pump priming, blood vessels of all mice were collected for staining, and the incidence of the sandwich was counted.
Tissue frozen section preparation:
at the end of the experiment, the mice were sacrificed under pentobarbital (100mg/kg) anesthesia and cardiac perfusion was performed with heparinized physiological saline to remove residual blood from the heart. The perfusion is continued with 4% paraformaldehyde to fix the vascular tissue morphology in situ. Separating and shearing the aortic arch part and the descending part under a stereomicroscope, soaking and fixing in 4% paraformaldehyde for 2 hours, transferring to 30% sucrose solution, standing overnight at 4 ℃, and fully dehydrating. The blood vessel is taken out from the sucrose solution in the next day, tissue moisture is fully absorbed by filter paper, the blood vessel is vertically embedded in the OCT embedding medium, and the tinfoil paper is slowly frozen in liquid nitrogen after being wrapped and can be stored in a refrigerator at the temperature of minus 80 ℃. Serial frozen tissue sections were performed, 5 μm thick, and the slides were coated with polylysine.
Preparation of Paraffin section of tissue
At the end of the experiment, the mice were sacrificed under pentobarbital (100mg/kg) anesthesia and cardiac perfusion was performed with heparinized physiological saline to remove residual blood from the heart. Separating and shearing the aortic arch part under a stereomicroscope, and fixing the aortic arch part in a 10% formaldehyde solution; normal aorta and TAD tissues were fixed in 10% formaldehyde solution. After at least 24 hours the vessels were removed for dehydration and the tissues were embedded in paraffin (vessels facing vertically downwards). The sections were cut continuously, 5 μm thick, and the slides were coated with polylysine.
And (3) histopathological detection:
I. the condition of the elastic plate is observed through dyeing the elastic fiber,
the specific operation is as follows:
1. freezing and slicing:
(1) washing OCT in frozen section PBS;
(2) adding 1 drop (100 μ l) of Lugol iodine solution (reagent A), incubating for 5min, and washing with water slightly;
(3) 1 drop (100. mu.l) of sodium thiosulfate (reagent B) was added for 5 minutes;
(4) washing with running water for 5min, and slightly washing with 70% alcohol;
(5) 1 drop (100. mu.l) of aldehydic magenta dye (reagent C) was added, and the resulting mixture was stained for 10 minutes, rinsed 2 times with 70% ethanol (about 30 seconds each time until the section was no longer decolorized), and washed with water;
(6) adding 1 drop (100 μ l) of orange G dye solution (reagent D) for dyeing for 10 seconds, and slightly washing with water;
(7) dehydrating with 95% ethanol for 5 min;
(8) dehydrating with anhydrous alcohol for 5 min;
(9) transparent xylene for 5min, and sealing;
2. paraffin section:
(1) paraffin sections were conventionally dewaxed with xylene, and were dewaxed to water with various levels of ethanol: xylene I (20min) → xylene II (20min) → xylene III (20min) → 100% alcohol (5min) → 95% alcohol (5min) → 80% alcohol (5min) → tap water washing off the alcohol.
(2) Adding 1 drop (100 μ l) of Lugol iodine solution (reagent A), incubating for 5min, and washing with water slightly;
(3) 1 drop (100. mu.l) of sodium thiosulfate (reagent B) was added for 5 minutes;
(4) washing with running water for 5min, and slightly washing with 70% alcohol;
(5) 1 drop (100. mu.l) of aldehydic magenta dye (reagent C) was added, and the resulting mixture was stained for 10 minutes, rinsed 2 times with 70% ethanol (about 30 seconds each time until the section was no longer decolorized), and washed with water;
(6) adding 1 drop (100 μ l) of orange G dye solution (reagent D) for dyeing for 10 seconds, and slightly washing with water;
(7) dehydrating with 95% ethanol for 5 min;
(8) dehydrating with anhydrous alcohol for 5 min;
(9) transparent xylene for 5min, and sealing;
the spandex appeared bluish purple and the background appeared yellow to varying degrees, as observed with a Nikon ECLIPSE 90i microscope. The inner side of the elastic plate is a neointimal part.
II, observing the structural damage condition of the blood vessel wall by HE staining,
the specific operation is as follows:
1. freezing and slicing:
(1) washing OCT in frozen section PBS;
(2) 4% paraformaldehyde was fixed for 10min and washed 3 times with PBS.
(3) Hematoxylin staining (1-2min), tap water three times to remove the loose color.
(4) The differentiation solution was washed with HCl for 2 seconds (twice), and then rewetted with tap water at a low flow rate (5 min).
(5) Staining with eosin (1-2min) for cytoplasmic staining, and washing with tap water to remove floating color (30 sec).
(6) Conventional dehydration, transparency, mounting: 80% alcohol (5min) → 95% alcohol (5min) → 100% alcohol (5min) → xylene I (5min) → xylene II (5min) → neutral gum blocking.
(7) The morphology of the specimen was observed under a microscope.
2. Paraffin section:
(1) paraffin sections were conventionally dewaxed with xylene, and were dewaxed to water with various levels of ethanol: xylene I (20min) → xylene II (20min) → xylene III (20min) → 100% ethanol (5min) → 95% ethanol (5min) → 80% ethanol (5 min).
(2) Washing with tap water, and washing with alcohol.
(3) Hematoxylin staining (3-5min), tap water three times to remove the loose color.
(4) The differentiation solution was washed with HCl for 2 seconds (twice), and then rewetted with tap water at a low flow rate (5 min).
(5) Staining with eosin (2-3min) for cytoplasmic staining, and washing with tap water to remove floating color (30 sec).
(6) Conventional dehydration, transparency, mounting: 80% alcohol (5min) → 95% alcohol (5min) → 100% alcohol (5min) → xylene I (5min) → xylene II (5min) → neutral gum blocking.
(7) The morphology of the specimen was observed under a microscope.
The results showed that the survival of the mice in the sinomenine-protected group was significantly improved compared to the mice in the control group (fig. 1A), and the incidence of arterial rupture and dissection was also significantly reduced (fig. 1B, C). The ultrasound results showed a significant decrease in the rate of vessel diameter expansion (fig. 1D). The blood vessel staining result of the mouse model shows that the artery lumen of the mouse in the sinomenine prevention group is relatively complete and round and is not expanded, the elastic plate on the inner wall of the blood vessel of the mouse in the control group is disordered, the diameter of the blood vessel is increased by more than 150 percent (obvious aortic aneurysm symptom), meanwhile, the elastic plate on the inner wall of part of the blood vessel is broken, and a large amount of sandwich thrombus appears in the artery blood vessel wall (figure 1E).
EXAMPLE 3 therapeutic Effect of Sinomenine administration on aortic dissection/aneurysm
TAD mouse models were constructed using the BAPN feeding method as described in example 1.
TAD-induced mice were randomly divided into two groups,
one group is a sinomenine experimental group: intraperitoneal injection of sinomenine is carried out once a day from 14 th day of feeding of BAPN-containing water according to a dose of 150 mg/kg;
the other group was a control group: the same volume of saline was administered by intraperitoneal injection at the same frequency as in the sinomenine-treated group.
Four weeks later, both groups of mice were given angiotensin ii (aii) pump charges for 24 h.
Post-dose observations include:
1. weight: two groups of mice were weighed daily. Observe whether the drug affects body weight versus growth.
BAPN uptake: observing the drinking conditions of the two groups of mice approximately every day, and judging whether the drug affects the weight change of the mice
3. Blood pressure changes: blood pressure measurements were taken every 3 days from the third week to exclude the effects of blood pressure changes on the risk of aneurysm \ dissection rupture and survival of the mice.
And (4) observing an end point:
1. mice spontaneously died during molding: record the time of death and the cause of death (whether or not it died due to interlayer rupture);
2. non-dead mice: performing aortic arch portion ultrasound on the living mouse 24h before pumping, and counting the diameter of a blood vessel; the mice were sacrificed 24h after pump priming, blood vessels of all mice were collected for staining, and the incidence of the sandwich was counted.
Frozen sections, paraffin sections, and histopathological examination were performed as in example 3.
The results showed that the survival of the mice in the sinomenine-treated group was significantly improved compared to the mice in the control group (fig. 2A), and the incidence of arterial rupture and dissection was also significantly reduced (fig. 2B, C). The ultrasound results showed a significant decrease in the rate of vessel diameter expansion (fig. 2D). The results of blood vessel staining of the mouse model showed that the arterial lumen of the mice in the sinomenine-treated group was relatively intact and did not dilate, the elastic plates on the inner walls of the blood vessels of the mice in the control group were disordered, the diameter of the blood vessels increased by over 150% (significant symptoms of aortic aneurysm), and at the same time, the elastic plates on the inner walls of some blood vessels broke open, and a large amount of sandwich thrombus appeared in the arterial blood vessel wall (fig. 2E).
Finally, it should be noted that the above examples are only used to help those skilled in the art understand the spirit of the technical solution of the present invention, and do not limit the scope of the present invention.
Claims (2)
1. The sinomenine is used as the only active component in the preparation of the medicine for preventing the thoracic aorta interbedded, and the sinomenine is sinomenine hydrochloride.
2. The use of claim 1, wherein the medicament is: drugs administered via the gastrointestinal tract, drugs administered via intravenous injection, and drugs administered via subcutaneous embedding administration.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1981763A (en) * | 2005-12-16 | 2007-06-20 | 杏林科技有限公司 | Antineoplastic usage of sinomenine and its preparation |
| CN101347408A (en) * | 2008-09-05 | 2009-01-21 | 李蕴麟 | Kukoline intravenous transfusion preparation |
| CN105748479A (en) * | 2016-02-04 | 2016-07-13 | 浙江工业大学 | Application of sinomenine in preparation of medicament for preventing and treating myocardial hypertrophy |
| CN106361751A (en) * | 2016-11-07 | 2017-02-01 | 北京市心肺血管疾病研究所 | Application of berberine in prevention and treatment of thoracic aortic dissection/aortic aneurysm |
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| AU2017101212A4 (en) * | 2017-09-05 | 2017-10-05 | Macau University Of Science And Technology | Method of selectively inhibiting mpges-1 |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1981763A (en) * | 2005-12-16 | 2007-06-20 | 杏林科技有限公司 | Antineoplastic usage of sinomenine and its preparation |
| CN101347408A (en) * | 2008-09-05 | 2009-01-21 | 李蕴麟 | Kukoline intravenous transfusion preparation |
| CN105748479A (en) * | 2016-02-04 | 2016-07-13 | 浙江工业大学 | Application of sinomenine in preparation of medicament for preventing and treating myocardial hypertrophy |
| CN106361751A (en) * | 2016-11-07 | 2017-02-01 | 北京市心肺血管疾病研究所 | Application of berberine in prevention and treatment of thoracic aortic dissection/aortic aneurysm |
Non-Patent Citations (1)
| Title |
|---|
| 青藤碱对动脉粥样硬化兔及其体重的影响;张绍兰等;《内蒙古中医药》;20141231(第10期);第105-106页 * |
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